GENERAL GUIDELINES FOR SAFETY/TOXICITY
GUIDELINES SERIES-IIGENERAL GUIDELINES FORSAFETY/TOXICITYEVALUATION OFAYURVEDIC FORMULATIONSCENTRAL COUNCIL FOR RESEARCH IN AYURVEDIC SCIENCESM in istry o f AYUSH, G o v ern m en t o f IndiaN ew D elh i
RAL GUIDELINES FORSAFETY/TOXICITYEVALUATION OFAYURVEDIC FORMULATIONSVolume - IICENTRAL COUNCIL FOR RESEARCH IN AYURVEDIC SCIENCESMinistry of AYUSH, Govt, of IndiaNew i
llllllllllllllllllllllllllllllllllllllllllllll Central Council for Research in Ayurvedic SciencesMinistry of AYUSH, Government of India, New Delhi - 110058First Edition - 2018Publisher: Central Council for Research in Ayurvedic Sciences, Ministry of AYUSH, Government ofIndia, New Delhi, J. L. N. B. C. A. H. Anusandhan Bhavan, 61-65, Institutional Area, Opp. D-Block,Janakpuri, New Delhi - 110 058, E-mail: dg-ccras@nic.in, Website : www.ccras.nic.inDisclaimer: All possible efforts have been made to ensure the correctness of the contents. HoweverCentral Council for Research in Ayurvedic Sciences, Ministry of AYUSH, shall not be accountablefor any inadvertent error in the content. Corrective measures shall be taken up once such errors arebrought to notice.ISBN : 978-93-83864-24-9Other Related Guidelines:Volume-I: General Guidelines for Drug Development of Ayurvedic FormulationsVolume - I I I : General Guidelines for Clinical Evaluation of Ayurvedic InterventionsPrinted a t : JK Offset Graphics Pvt. Ltd., New iiiiiiii
OGUER&D in the field of AYUSH system in different areas such as drug development includingquality assurance, pre-clinical safety evaluation and clinical research are being conducted atdifferent levels such as Research Council under AYUSH, Academic institutions (bothAYUSH and non AYUSH institutes such as Medical Colleges, Universities etc.), otherResearch organization such as ICMR, CSIR etc. Further, research support is also beingextended through grant under EMR vide Ministry of AYUSH, DST, DBT, ICMR etc. in thearea of traditional medicine.Lot of research is being conducted at different levels as above in the field of AYUSHadopting different guidelines, methods and protocols and ending up research outcomes withlow or poor translational value. Only few of them have led to clinical trial and marketinglevel. This may be attributed to lack of awareness regarding AYUSH strategies for R&D andprovisions of Drug & Cosmetic Act related to AYUSH.In spite of availability of several guidelines such as GCP guidelines for ASU drugs,ICMR guidelines for bio medical research for human participants, GCP guidelines publishedby CDSCO Ministry of Health and Family Welfare, WHO guidelines for traditional medicalresearch etc., there is no single comprehensive guidline to conduct research in AYUSHsector is available.This might be one among the major reasons that has led to R&D in AYUSH sectorwith diverse approaches with low translational value.In view of this, it becomes imperative to develop directives on research practices forvarious components of AYUSH research sectors for uniform adoption across all stake holderssuch as research councils, academic institutes, funding agencies engaged in AYUSHresearch.CCRAS developed three comprehensive and concise Guidelines focusing on drugdevelopment (Standardization and quality assurance), safety/toxicity and clinicalevaluation for ready reference o f stakeholders. These Guidelines encompassed researchpractices generally to be adopted and followed by researchers in the field o f AYUSHsystem such as research organizations, academic institutions and researchers seeking grantfrom EMR/IMR schemes o f different funding agencies for research on AYUSH system,and would help the researchers while designing and formulating the proposals and alsoplanning academic/ industrial research in the field o f AYUSH systems. The users may referto other two documents for having an overall idea concerning drug development and R & Din this ii
GROUNDQuests for healthy and long life are perhaps as old as human existence and efforts areunremitting to address the challenges and triumph over the bottlenecks across this journey.Ayurveda -the science of life, evolved as a comprehensive system of healthcaresystematically through scientific experimentations of high order backed by sound andreproducible evidence base and stood the test of the time. Several strategies and road mapsare being drawn to carry forward merits of this science so as to meet the current day heathneeds and mainstream its core strengths alongside through research & development in thiscountry and across the globe. The fundamental aspects of holistic systems needs adequatepositioning, while designing clinical trials to examine the safety and efficacy of Ayurveda.Furthermore, the other challenges and issues related to quality, safety, dosage forms/deliverysystem, diverse concepts and complex approaches in trial design, diagnosis and therapy,outcomes of clinical efficacy and drug interactions also pose certain limitations in research. Asystems approach may be adopted to validate the therapies with integration of principles ofAyurveda and bio-medicine without losing the vital fundamentals of both systems. Such anapproach with well designed research plans could possibly facilitate to generate tangibleevidence.The roots of experimentation for ensuring safety of food and drugs have been invogue since ancient times. There are evidences that Ayurveda is well versed with thepreclinical testing i.e. Vishanna/Virudhanna Pareeksha conducted on animals. Sushrutamentioned the animal experiments like testing the food/drug by giving it to the animal likebirds (pigeon, peacock), animals (rabbit, monkey) in order to establish the safety and toxicity.Charak Samhita elaborates the importance of safety of a medicine by defining that medicineis safe and effective, if it alleviates the disease and does not produce any concomitant badeffect. In Ayurveda, plants, animal products and minerals based medicines are used forhealthcare and treatment of various disease conditions.It was known to ancient Ayurvedic scholars that metals, minerals and some plants aretoxic and harmful to the body and therefore, it was advocated to process them properly so asto render them therapeutically safe. Ayurveda pharmaceutics strongly recommend variousother safety aspects, which are known for their contemporary relevance, like GoodAgricultural Practices (GAP), Good Field Collection Practices (GFCP) of medicinal plantsand Good Manufacturing Practices (GMP) for preparation of quality assured drugs. Factorslike place, soil, season and time for collection of natural drugs also play a significant role inthe quality, strength and purity of drugs.With tremendous expansion in the use of natural products, globally, safety andefficacy as well as quality control of ASU drugs have become pivotal concern for both healthauthorities and public in general.Nonclinical evaluation of drug safety usually consists of standard animal toxicologystudies. Animal toxicity studies need to be carried out to assess the potential undesirablepharmaco-dynamic effects of drugs on physiological functions in relation to exposure withinthe therapeutic ii
llllllllllllllllllllllllllllllllllllllllllllllThe development of a drug is a stepwise process involving an evaluation of bothanimal and human efficacy and safety information. The goals of the nonclinical safetyevaluation generally include characterization of toxic effects with respect to target organs,dose dependence, relationship to exposure, and, when appropriate, potential reversibility.This information is used to estimate an initial safe starting dose and dose range for the humantrials and to identify parameters for clinical monitoring for potential adverse effects.Before conducting any toxicological testing in animals, the study should be approvedby the Institute Animal Ethics Committee (IAEC) or the protocol should satisfy theguidelines of the local governing body. In India, the Committee for the Purpose of Controland Supervision of Experiments on Animals (CPCSEA) guidelines should be followed for themaintenance of experimental animals.However, Ayurvedic drugs are prescribed considering various aspects viz. Anupana,Dose, Dosage, Age etc. which may play pivotal role in their therapeutic potential. Further, itis pertinent to say that some drugs are used after processing such as Shodhna, Marana.Therefore, safety/ toxicity studies of such drugs may only be conducted adopting similarAyurvedic procedures. Hence, there is a need for fundamentally different approach fortoxicological studies that need to be adopted for ASU drugs.Owing to the importance of safe use of ASU drugs, Ministry of AYUSH has issuedguidelines for licensing of these drugs vide Gazette notification Rule 158B, dated 10th august,2010 wherein, the safety requirements for different categories of ASU drugs are described.Despite existence of several guidelines such as General Methodologies & Researchevaluation Traditional Medicines, OECD guidelines, Schedule Y of Drug and Cosmetic Actetc., GCP Guidelines for ASU Medicines, there is a need to evolve a comprehensiveguideline to address system specific issues for conducting safety/toxicity studies of ASUdrugs. The present document would certainly serve as a ready reference for researchersengaged in Research and Drug development in ASU iiii
llllllllllllllllllllllllllllllllllllllllllllllLIST OF ABBREVIATIONSLD50 : Median Lethal DoseNOEL: No Observed Effect LevelNOAEL: No Observed Adverse Effect LevelOECD: Organization of Economic Cooperation and DevelopmentCPCSEA: Committee for the Purpose of Control and Supervision of Experiments on AnimalsIAEC: Institutional Animal Ethics CommitteeGLP: Good Laboratory PracticeABHF: Animal Breeding and Housing FacilityWBC: White blood cell countRBC: Red blood cell countHGB: Hemoglobin concentrationHCT: HematocritMCV: Mean corpuscular volumeMCH: Mean corpuscular hemoglobinMCHC : Mean corpuscular hemoglobin concentrationCHCM: Cellular hemoglobin concentration meanCH: Cellular hemoglobinHDW: Hemoglobin concentration distribution widthRDW: Red cell distribution widthPLT: Platelet countMPV: Mean platelet volumeDLC: Differential leucocytes countNAD: No abnormalities detectedXALB: AlbuminTBIL: Total BilirubinCHOL: CholesterolCREA: CreatinineG LU : GlucoseTP: Total ProteinTGL : TriglyceridesALT: Alanine aminotransferaseAST: Aspartate aminotransferaseALP: Alkaline PhosphataseGGT : Gamma glutamyl transferaseC PK : Creatinine phosphokinaseLDH: Lactate dehydogenaseCOA : Certificates of AnalysisM: E : Myeloid: Erythroid i
ENTSPrologueiiiBackgroundivList of AbbreviationsviLIST OF CHAPTERS1.General Research Guidelines And Methodologies For DrugDevelopment at a glance12.Single-Dose Toxicity Studies (Acute Toxicity)53.Repeated-Dose Toxicity Studies64.Reproductive and Developmental Toxicity115.Special Toxicity155.1 Genotoxicity155.2 Carcinogenicity165.3 Local Toxicity Test for Topical preparations186.References217.Suggestive Readings228.Glossary239.Annexures249.1158(B) Guidelines for issue o f license with respect toAyurveda, Siddha or Unani drugs249.2 Guidelines on the regulation o f scientific experiments onanimals329.3 CPCSEA Guidelines for Laboratory Animal Facility-2005459.4 Expert involved in development o f Guidelines andconsultative iiiii
1.GENERAL RESEARCH GUIDELINES AND METHODOLOGIES FOR DRUG DEVELOPMENT AT A GLANCEPREPARATORY PHASE (11Prevalence survey andFormulation of drug/combination forSpecific targeted indication n/activity (1)(Appropriate basis of literary survey, Previous clinical data of ingredients/any other data of claims, classicalEvidences)Formulation of SOPs andStandardization, stability studiesQuality assurance drug (4) (Considering the classical methodsand current available physical/chemical-1, Biological parameters,for standardization).Design of study and Formulation ofClinical protocols (7) (considering(As per current guidelines and adoptingClassical methodology.)Finalization with task force of expertsBulk preparation of quality assuredDrug for clinical trial, packinglabeling etc. as per need atDRUG DEVELOPMENT PHASES (2-81Collection ofraw drugs (2)(considering currentgood agricultural practicesgood field collection practicesand Ayurvedic textual methods)Botanical identification/Pharmacogonostic/Chemical studies ofingredients. (3)(based on available guidelines and classical methodology.)Non clinical safety studies (5)(acute/subacute/chronic studiesas per the clinical use of the drug)(with appropriate animal ethicalclearances as per available guidelines )Animal Studies for biological activity/efficacy (specific/mechanism of action,activity for clinical co relation) (6)Execution of Clinical Trial (8)Approval of IEC/IRB and CTRI registrationTrial conductTrial monitoringTrial coordinationData analysisPublicationNote: IPR Protection and issues of filing of patent to be addressed at suitable stage.
Table 1: Research criteria for evaluating the safety/toxicity of ASU drugsRequirement of Non- Requirement of NonS. No. CategoryIngredient(s)Indication(s)clinical Safety dataclinical Efficacy Data(2)(3)(4)(5)(6)(1)Classical ASU drugs as defined under Section 3 (a) of the Drugs and Cosmetics Act, 1940As per textNot RequiredNot Required1.1 Ayurvedic, Siddha and As per text1.Unani drugs given in 158B asreferred in Section 3(a) ofDrugs and Cosmetics Act,1940As per textNot RequiredNot Required1.2 Any change in dosage As per textform of ASU Drugs asdescribed in Section 3(a) ofDrugs and Cosmetics Act,1940NewNot RequiredRequired1.3 ASU Drugs referred in As per textsection3(a) of Drugs andCosmetics Act, 1940 to beused for new indication*Patent or Proprietary Drugs as defined under section 3(h) of the Drugs and Cosmetics Act, 19402.2.1 Patent or Proprietary Drugs as As per textdefined under section 3(h) ofDrugs and Cosmetics Act, 1940containing crude drugs /AqueousExtract(s) / Hydro-AlcoholicExtracts).Textual rationaleNot requiredNot required
2.2 Patent or Proprietary Drugs as As specifieddefined under section 3(h)containing other than Aqueousand Hydro-alcoholic extract(s) /any other solvent based extract(s)*2.4 Patent or Proprietary Drugs as As per textdefined under section 3(h)containing any of the ingredientsof ScheduleE (1) of the D&CAct, 1940Required/ Required:For Oral preparations*1. Single dose toxicity test(Acute toxicity) in mice andrats.2. Repeated-dose SystemicToxicity Studies (long termtoxicity studies in 4. Genotoxicity5. Carcinogenicity*metal associated toxicity incase of any metal/mineral asone of the ingredientFor topical preparationsa) Dermal toxicity study.b) Photo-allergy or ity in guinea pigsIndicationas For oral preparationsRequiredclaimed / specified1. Single dose toxicity test(Acute toxicity) in mice andrats.2. Repeated-dose SystemicToxicity Studies (long termAsspecifiedclaimed
toxicity studies) in two speciesone rodent(rat) and one non rodent tudies4.Genotoxicity5. Carcinogenicity*metal associated toxicity incase of any metal/mineral asone of the ingredientFor Topical preparationsa) Dermal toxicity study.b) Photo-allergy or ity in guinea pigs
INIIINIIINIIIIIIINI2.1SINGLE-DOSE ACUTE TOXICITY STUDYSINGLE-DOSE TOXICITY STUDIES (ACUTE TOXICITY): Acute toxicitystudies aim to determine toxic manifestations of the test substance that occur whenanimals are exposed to one or more doses within a 24-hour period.2.1.1 Animal species: These studies should be carried out in two rodent species, mice andrats2.1.2 Sex: Both, males and females (nulliparous and non pregnant) should be used2.1.3 Number of animals: Each group should consist of at least six animals per sex.2.1.4 Dose levels and route of administration: The limit of 2gm/kg or at least 10 times ofthe intended clinical therapeutic dose whichever is less, using the same route asrecommended for human.2.1.5 Frequency of administration: The test substance should be administered in one ormore doses during a 24-hour period.2.1.6 Study observations: Toxic signs and the severity, onset, progression and reversibilityof the signs and mortality, if any, for 14 days after administration of test compound.Additional observations will be necessary if the animals continue to displaysigns of toxicity. Observations should include changes in skin and fur, eyes andmucous membranes, and also respiratory, circulatory, autonomic and central nervoussystems, and somatomotor activity and behaviour pattern. Attention should be directedto observations of tremors, convulsions, salivation, diarrhoea, lethargy, sleep andcoma. Animals found in a moribund condition and animals showing severe pain orenduring signs of severe distress should be humanely killed. When animals are killedfor humane reasons or found dead, the time of death should be recorded as precisely aspossible. Autopsy of any animal which dies during study period has to be done. Ifnecessary, a histopathological examination should be conducted on any organ/tissueshowing macroscopic changes at autopsy.2.1.7 Result: Body weight/body weight changes; Tabulation of response data and dose level for each animal (i.e., animals showingsigns of toxicity including nature, severity, duration of effects, and mortality); Individual weights of animals at the day of dosing, in weekly intervals thereafter,and at the time of death or sacrifice ; Time course of onset of signs of toxicity and whether these were reversible foreach animal; Necropsy findings and any histopathological findings for each animal, if available; Maximum tolerated dose may be calculated. Statistical treatment of results (description of computer routine used andspreadsheet tabulation of calculations).General Guidelines for Safety/Toxicity Evaluation of Ayurvedic Formu
Ayurveda and bio-medicine without losing the vital fundamentals of both systems. Such an approach with well designed research plans could possibly facilitate to generate tangible . It was known to ancient Ayurvedic scholars that metals, minerals and some plants are toxic and harmful to the
Bruksanvisning för bilstereo . Bruksanvisning for bilstereo . Instrukcja obsługi samochodowego odtwarzacza stereo . Operating Instructions for Car Stereo . 610-104 . SV . Bruksanvisning i original
10 tips och tricks för att lyckas med ert sap-projekt 20 SAPSANYTT 2/2015 De flesta projektledare känner säkert till Cobb’s paradox. Martin Cobb verkade som CIO för sekretariatet för Treasury Board of Canada 1995 då han ställde frågan
service i Norge och Finland drivs inom ramen för ett enskilt företag (NRK. 1 och Yleisradio), fin ns det i Sverige tre: Ett för tv (Sveriges Television , SVT ), ett för radio (Sveriges Radio , SR ) och ett för utbildnings program (Sveriges Utbildningsradio, UR, vilket till följd av sin begränsade storlek inte återfinns bland de 25 största
Hotell För hotell anges de tre klasserna A/B, C och D. Det betyder att den "normala" standarden C är acceptabel men att motiven för en högre standard är starka. Ljudklass C motsvarar de tidigare normkraven för hotell, ljudklass A/B motsvarar kraven för moderna hotell med hög standard och ljudklass D kan användas vid
LÄS NOGGRANT FÖLJANDE VILLKOR FÖR APPLE DEVELOPER PROGRAM LICENCE . Apple Developer Program License Agreement Syfte Du vill använda Apple-mjukvara (enligt definitionen nedan) för att utveckla en eller flera Applikationer (enligt definitionen nedan) för Apple-märkta produkter. . Applikationer som utvecklas för iOS-produkter, Apple .
Second Edition (USEPA, 1991a), Marine Toxicity Identification Evaluation (TIE) Guidance Document, Phase I (USEPA, 1996), Methods for Aquatic Toxicity Identification Evaluations: Phase II Toxicity Identification Procedures for Samples Exhibiting Acute and Chronic Toxicity (USEPA, 1993a), and Methods
to predict the incidence of severe toxicity grade 4 hematologic or grade 3 to 4 non hematologic toxicity (as defined by the National Cancer Institute-Common Toxicity Criteria (NCI-CTC version 3)) [16] and/or chemotherapy interruption related to unacceptable toxicity
Fish toxic test guideline OECD guidelines for the testing of chemicals 210: Fish early-life stage toxicity test 215: Fish juvenile growth test 229: Fish short term reproduction assay 236: Fish embryo acute toxicity (FET) test 305: Bioaccumulation in fish aqueous and dietary exposure EPA OPPTS 850.1075: Fish acute toxicity test
